Major Advances in RET Inhibition for NSCLC and MTC - Episode 4

Use of Liquid Biopsy for RET Detection


Benjamin P. Levy, MD: I’m not getting away with doing 1 of these without talking about plasma. What we’ve learned from some critical data sets is that when you add plasma to tissue at the same time from the same patient, you increase your likelihood of detecting an alteration of interest, which would allow you to give targeted therapies. Tissue is fraught with challenges. It is still the gold standard in my mind, but it certainly is fraught with challenges in terms of heterogeneity depending on where the needle is, tissue sufficiency. You mentioned tissue stewardship, immuno-stained tissue exhaustion. The journey the tissue takes from procurement from the lung to the pathologist and the result is quite incredible. There are so many steps along the way where things can go wrong and enters plasma. It’s an easy test to do. You’ve heard me say this joke before: You and I may have a tough time identifying a good interventional radiologist, but we all know a good phlebotomist. And you know, 10 cc of blood, and we’ve learned that adding blood to tissue can enhance capture of alterations that leads to targeted-therapy treatment.

But the question comes up, and I’d just be curious to know—fusion detection in plasma maybe a little harder than just mutations—your experience with plasma and how you see this all playing out now and in the future for all mutations but also for RET.

Jared Weiss, MD: You and I have spoken about this over time. I will confess to you, however many of our friends are watching this, that I was a little wrong on plasma. My feelings on it have evolved as data have evolved. I was a little skeptical of plasma when it was new, and increasingly I’ve come around to your viewpoint that it’s very much additive. It’s additive when you have a lack of tissue. You can sometimes find things that you don’t find in tissue, particularly in addressing heterogeneity. In my practice, what is most relevant is that it’s fast, right? You talked about the journey of tissue. At some institutions it can take a week or 2 from biopsy to getting that tissue in the mail, never mind the amount of time it takes to do a comprehensive next-generation platform. There is a tremendous role for plasma. I do think that when we’re talking about fusions like RET, this is a place where it’s weaker in terms of sensitivity. If you pick it up, it’s real. You can action it. You don’t have to question that, but if you don’t find it and you don’t find another oncogene driver, then you have to go to a good tissue-based test. What I mean by that is that a test can be negative in 2 ways, right? If I send off a liquid test, and I get KRAS G12V, it’s negative in the sense that I can’t do anything with that to help my patient. I’m bummed out, but I can be done. I know the answer. I don’t like the answer, but I know the answer. On the other hand, if I don’t find anything that’s a clear driver, that’s when it’s really important to go to tissue for greater sensitivity.

Benjamin P. Levy, MD: Great point. Knowing that a negative really doesn’t tell you anything—a positive, you can kind of rule in. But for a negative, in terms of negative driver mutation or known driver or known alteration, you need to reflex the tissue. That’s an important point. The thing that also comes up is not just the routine use of plasma, but also how often should we be doing next-generation sequencing on our patients? Is it just at 1 point, or is it through a continuum? For me, we’re just starting to learn about mechanisms of resistance for RET fusions in lung cancer with gatekeeper mutations and mirroring some of the things that we’re doing in ALK, RAS, and EGFR. I tend to want to know, at least from a research standpoint, what’s going on for patients. Now I will be transparent. Of all the patients we’ve had on selpercatinib, who are RET-fusion-positive, they haven’t progressed. But I don’t have a lot of experience with rebiopsying these patients. What are your thoughts on that? Do you rebiopsy patients upon progression for all targeted therapies? Should we do it for RET patients?

Jared Weiss, MD: We’re doing it sometimes because we’re an academic institution and that’s what we’re here to do. But when I counsel patients about this, I do counsel them that it may not be actionable. It may not be useful clinically. I tend to use a little more liquid here because even knowing the limitations of liquid that we’ve talked about, at least I don’t have a risk of hurting my patient in doing it. But honestly, if 1 of our community partners said, “I’m just not doing that now,” there is nothing wrong with not retesting in the case of RET on progression because we don’t know what to do with it.

Transcript Edited for Clarity